The ability to bind, store, and retrieve complex multi-modal associations a critical feature of human memory. This ability requires mechanisms by which the brain can link information that is initially processed in distinct, non-overlapping cortical circuits in a manner enabling the efficient retrieval desired information. A growing consensus in the cognitive neuroscience of memory, inspired by anatomical, empirical, and theoretical considerations, posits that the hippocampus receives input from association cortices and through its'internal circuitry links this information such that later retrieval of the diverse kinds of information encoded in human memories is possible. This model holds that presentation of a retrieval cue elicits activity in the hippocampal ensemble active during the original episode and this activity leads in turn to the reactivation of cortical areas processing the information contained in the memory. Although there are data supporting pieces of this model, there is as yet no direct evidence linking activity in the hippocampus to the subsequent reactivation of cortex nor specification of the means by which these retrieval processes are strategically modulated in the service of retrieving those aspects of our memories which are relevant in the current behavioral context. As the hippocampal system plays a critical role in supporting these memory processes, and given the susceptibility of this system to insult from stroke, epilepsy, and aging, understanding of these core memory processes is a fundamental goal of cognitive neuroscience. This proposal uses a combination of the temporal specificity afforded by magnetoencephalography (MEG) and the spatial precision of functional magnetic resonance imaging (fMRI) to ask whether hippocampal processes lead to cortical reactivation during memory retrieval and whether these cortical reactivations can be strategically modulated when the desired contents of memory are known. In Aim 1 MEG will be used to compare the timing of hippocampal retrieval signals and reactivation of content-specific cortical areas to assess the role of the hippocampus in driving mnemonic activity in neocortex. Aim 2 will utilize fMRI to ask whether presentation of a cue leads automatically to the retrieval of associations of that cue, as assessed by cortical reactivation, or whether the retrieval process can be targeted or modulated by current task demands. Together, these experiments will provide important insights into the cortico-hippocampal interactions underlying much of our memories and will test critical and undersupported assumptions in current models of memory function. By expanding our knowledge of basic mechanisms of memory retrieval, this work will contribute knowledge that is essential for understanding the deficits associated with disruption to this system. PUBLIC HEALTH RELEVANCE: This proposal seeks to specify the means by which the hippocampus and cortex interact in the service of retrieving information from memory. This work is relevant to public health as the hippocampal system is particularly susceptible to damage or deterioration from epilepsy, strokes, and aging. As disruptions to memory processes have profound effects on quality of life and the ability to act in the world, understanding of these core mechanisms will provide crucial insights into the nature and extent of such disruptions and enable the increasingly sophisticated and targeted development of behavioral and physiological therapies.